Association Analysis of Genetic Polymorphisms in the CDC2 Gene with Late-Onset Alzheimer Disease

Abstract

Background: Alzheimer disease (AD) is a complex neurodegenerative disorder resulting from multiple genetic and non-genetic factors. Linkage studies indicated that chromosome 10 has at least one locus for this disease. The cell division cycle 2 (CDC2) gene, which is close to one of the linkage regions, has previously been associated with the risk of AD with an odds ratio of 1.78. Biologically, CDC2, which is involved in paired helical filament-tau formation, is thought as a candidate gene in AD. Methods: In this study, six single nucleotide polymorphisms spanning the entire gene were selected and examined for association for late-onset AD (LOAD) in two large independent datasets. A family-based dataset including 1,337 Caucasian discordant sib pairs and an independent dataset of 745 Caucasian cases and 998 controls for LOAD were used. Family-based association tests and logistic regression conditional on the apolipoprotein E genotype and sex were applied to association study in family-based and case-control datasets, respectively. Results: Neither dataset demonstrated any association with LOAD in our samples with all p values >0.16. Conclusion: Our results suggest that if any contribution of common genetic variants in CDC2 to the risk of developing AD exists, it is likely to be very small.

Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

“…CDC2 has been associated with AD and with increased levels of tau in cerebrospinal fluid (Johansson A et al, 2003;Johansson A et al, 2005). However, we were not able to replicate these findings in a previous analysis of our complete dataset (Liang X et al, 2007b). In cluster 1, the CDC2 marker rs2448341 was significant by its PDT and Pearson chi-square statistics.…”

Genetic Variation in the Tau Kinases Pathway May Modify the Risk and Age at Onset of Alzheimer's Disease

“…Late-onset AD patients might have a different genetic background compared with earlyonset AD patients that might enhance the effect of all these tau kinases pathway risk alleles, leading to a late expression of the disease. A polymorphism in the exon 6 (rs321239) of CDC2 was associated with AD risk in the Swedish population [19], and a haplotype derived from SNPs in exon 6 (rs321239) and exon 7 (rs2456777 and rs2456778) increased the risk of AD in APOE 4 carriers from Sicily [20], but a large study in Caucasian Americans failed to demonstrate this association [21]; conversely, a haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) of CDC2 showed a protective effect against AD in APOE 4 allele noncarriers in our population. The concentration of both activated CDC2 [22] and RPS6KBs [23] increases in AD brain and their distribution coincide with the progression of neurofibrillary degeneration.…”

A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75NTR

“…119,120 Besides being a source of superoxide anions 121 and pathogenic cytokines, 122 microglial cells can also express NGF/proNGF, [123][124][125][126] thus triggering NGF-dependent neurodegeneration. Microglial cells activated by inflammatory signals, including the Aβ fragment Aβ [25][26][27][28][29][30][31][32][33][34][35] , have been shown to express NGF, 127 and they induce cell cycle re-entry and cell death of cortical neurons in vitro. 128 regulating several cellular functions including cell survival, cell death and axonal outgrowth.…”

“…57 Indeed, the presence of double nucleated neurons, likely derived from nuclear division without cytokinesis, has been reported to occur in AD. 160 Interestingly, different polymorphisms of BDNF can confer risk of suffering AD, although their association with Interestingly, Aβ [25][26][27][28][29][30][31][32][33][34][35] can also induce NGF in astrocytes, which in turn triggers hyperphosphorylation of Tau in neurons, mediated by p75 NTR . 129 This suggests that general gliosis may participate in the progression of AD.…”

“…15 The presence of cdc2 and cyclin B in AD has been further confirmed by several authors; 5,7,[19][20][21] and, in line with this view, a cdc2 polymorphism has been suggested to be linked with late onset AD, [22][23][24] although this later observation is still under debate. 25 Apart from the observation that G 2 /M-specific regulators are detected in AD, direct evidence for S-phase progression in AD-affected neurons has also been reported. 26,27 These observations are consistent with the presence of hyperphosphorylated Rb and E2F1 immunoreactivity in AD brain, associated with neurons surrounding Aβ-containing plaques but not in NFT containing neurons, 28 thus suggesting that E2F1 activation takes place prior to the presence of neuropathological signs in neurons.…”